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US 5,668,279 AGranted
Substituted phthalazinones as neurotensin antagonists
AssigneeMerck & Co., Inc.
InventorsPrasun K. Chakravarty, Elizabeth M. Naylor, Anna Chen
Life of this patent
Estimating the term…
Abstract
Novel substituted phthalazinones of the formula (I) ##STR1## are useful as neurotensin antagonists.
Claims6
A compound of structural formula I:
- ##STR19## or a pharmaceutically acceptable salt thereof, wherein:
- R.sup.1 is:
- (a) --NHSO.sub.2 NHCOR.sup.9,
- (b) --NHCONHSO.sub.2 R.sup.9,
- (c) --SO.sub.2 NHR.sup.9,
- (d) --SO.sub.2 NHCOR.sup.9,
- (e) --SO.sub.2 NHCONR.sup.7 R.sup.9, or
- (f) --SO.sub.2 NHCOOR.sup.9 ;
- R.sup.2a and R.sup.2b are each independently:
- (a) H,
- (b) Cl, Br, I, F,
- (c) CF.sub.3,
- (d) C.sub.1 -C.sub.6 -alkyl,
- (e) C.sub.1 -C.sub.6 -alkoxy,
- (f) C.sub.1 -C.sub.6 -alkyl-S--,
- (g) C.sub.2 -C.sub.6 -alkenyl,
- (h) C.sub.2 -C.sub.6 -alkynyl,
- (i) C.sub.3 -C.sub.7 -cycloalkyl,
- (j) aryl, where aryl is as defined in R.sup.4 (c) below, or
- (k) aryl-C.sub.1 -C.sub.6 -alkyl, where aryl is as defined in R.sup.4 (c) below;
- R.sup.3a is:
- (a) H,
- (b) Cl, Br, I, F,
- (c) C.sub.1 -C.sub.6 -alkyl,
- (d) C.sub.1 -C.sub.6 -alkoxy, or
- (e) C.sub.1 -C.sub.6 -alkoxyalkyl;
- R.sup.3b is:
- (a) H,
- (b) Cl, Br, I, F,
- (c) C.sub.1 -C.sub.6 -alkyl,
- (d) C.sub.3 -C.sub.7 -cycloalkyl,
- (e) C.sub.1 -C.sub.6 -alkoxy,
- (f) CF.sub.3,
- (g) C.sub.2 -C.sub.6 -alkenyl, or
- (h) C.sub.2 -C.sub.6 -alkynyl;
- R.sup.4 is:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, optionally substituted with a substituent selected from the group consisting of:
- C.sub.1 -C.sub.4 -alkoxy, aryl, where aryl is as defined in R.sup.4 (c) below, heteroaryl, where heteroaryl is as defined below, --CON(R.sup.10).sub.2, --N(R.sup.10).sub.2, --O--COR.sup.10 and --COR.sup.10 or
- (c) aryl, wherein aryl is phenyl or naphthyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, F, Br, I, N(R.sup.7).sub.2, NR.sup.7 COOR.sup.9, NR.sup.7 CONR.sup.7 R.sup.9, CO.sub.2 R.sup.7, CONR.sup.7 R.sup.9, C.sub.1 -C.sub.4 -alkyl, --(C.sub.1 -C.sub.4)alkyl-Y, NO.sub.2, OH, CF.sub.3, C.sub.1 -C.sub.4 -alkoxy, --S(O).sub.X --(C.sub.1 -C.sub.4)alkyl, and --(C.sub.1 -C.sub.4)alkyl-N-(CH.sub.2 --CH.sub.2).sub.2 Q,
- (d) heteroaryl, wherein heteroaryl is defined as pyridyl, and wherein the heteroaryl is unsubstimted or substituted with one or two substituents selected from the group consisting of:
- --OH, --SH, --C.sub.1 -C.sub.4 -alkyl, --C.sub.1 -C.sub.4 -alkoxy, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --(C.sub.1 -C.sub.4 -alkyl), --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl) and --N(C.sub.1 -C.sub.4 -alkyl).sub.2, NR.sup.7 COOR.sup.9 and NR.sup.7 CONR.sup.7 R.sup.9,
- (e) C.sub.3 -C.sub.7 -cycloalkyl, or
- (f) --COaryl, where aryl is as defined in R.sup.4 (c) above;
- Q is:
- a single bond, --CH.sub.2 --, O, NR.sup.7, or S(O).sub.X ;
- Y is:
- COOR.sup.9, CN, NR.sup.7 COOR.sup.9 or CONR.sup.7 R.sup.9 ;
- R.sup.5 and R.sup.6 are independently:
- (a) H,
- (b) C.sub.1 -C.sub.6 -alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
- --OH, -guanidino, C.sub.1 -C.sub.4 -alkoxy, --N(R.sup.7).sub.2, COOR.sup.7, --CON(R.sup.7).sub.2, --O--COR.sup.7, -aryl, where aryl is as defined in R.sup.4 (c) above, -heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above, --S(O).sub.X --R.sup.9, -tetrazol-5-yl, --CONHSO.sub.2 R.sup.9,--SO.sub.2 NH-heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above, --SO.sub.2 NHCOR.sup.9, --PO(OR.sup.7).sub.2, --PO(OR.sup.8)R.sup.7, --SO.sub.2 NH--CN, --NR.sup.8 COOR.sup.9, morpholino, N-(C.sub.1 -C.sub.6 -alkyl)-piperazinyl, and --COR.sup.7,
- (c) --CO-aryl, where aryl is as defined in R.sup.4 (c) above,
- (d) --C.sub.3 -C.sub.7 -cycloalkyl,
- (e) Cl, Br, I, F,
- (f) --OH,
- (g) --OR.sup.9,
- (h) --C.sub.1 -C.sub.4 -Perfluoroalkyl,
- (i) --S(O).sub.X --R.sup.9,
- (j) --COOR.sup.7,
- (k) --SO.sub.3 H,
- (l) --NR.sup.7 R.sup.9,
- (m) --NR.sup.7 COR.sup.9,
- (n) --NR.sup.7 COOR.sup.9,
- (o) --SO.sub.2 NR.sup.7 R.sup.8,
- (p) --NO.sub.2,
- (q) --NR.sup.7 SO.sub.2 R.sup.9,
- (r) --NR.sup.7 CONR.sup.7 R.sup.9,
- (s) --OCONR.sup.9 R.sup.7,
- (t) -aryl, where aryl is as defined in R.sup.4 (c) above,
- (u) --NHSO.sub.2 CF.sub.3,
- (v) --SO.sub.2 NH-heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above,
- (w) --SO.sub.2 NHCOR.sup.9,
- (x) --CONHSO.sub.2 R.sup.9,
- (y) --PO(OR.sup.7).sub.2,
- (z) --PO(OR.sup.8)R.sup.7,
- (aa) -tetrazol-5-yl,
- (bb) --CONH(tetrazol -5-yl),
- (cc) --COR.sup.7,
- (dd) --SO.sub.2 NHCN,
- (ee) --CO-heteroaryl, where heteroaryl is as defined in R4(d) above,
- (ff) --NR.sup.7 SO.sub.2 NR.sup.9 R.sup.7,
- (gg) --N[CH.sub.2 CH.sub.2 ].sub.2 NR.sup.11,
- (hh) --N[CH.sub.2 CH.sub.2 ].sub.2 O, or
- (ii) -heteroaryl, where heteroaryl is as defined in R4(d) above;
- x is:
- 0. 1, or 2,
- R.sup.7 is:
- H, C.sub.1 -C.sub.5 -alkyl, aryl, or --CH.sub.2 -aryl, where aryl is as defined in R.sup.4 (c) above;
- R.sup.8 is:
- H, or C.sub.1 -C.sub.4 -alkyl;
- R.sup.9 is:
- (a) aryl, where aryl is as defined in R.sup.4 (c) above,
- (b) heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above,
- (c) C.sub.3 -C.sub.7 -cycloalkyl,
- (d) C.sub.1 -C.sub.8 -alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
- aryl, where aryl is as defined in R.sup.4 (c) above, heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above, --OH, --SH, C.sub.1 -C.sub.4 -alkyl, --O(C.sub.1 -C.sub.4 -alkyl), --S (C.sub.1 -C.sub.4 -alkyl), --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --C.sub.1 -C.sub.4 -alkyl, --NH.sub.2, --NR.sup.7 CO.sub.2 R.sup.10, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, --PO.sub.3 H.sub.2, --PO(OH)(O--C.sub.1 -C.sub.4 -alkyl), --PO(OR.sup.8)R.sup.7, --NR.sup.7 COR.sup.10, --CONR.sup.7 R.sup.10, --OCONR.sup.7 R.sup.10, --SO.sub.2 NR.sup.7 R.sup.10, --NR.sup.7 SO.sub.2 R.sup.10, --N(CH.sub.2 --CH.sub.2).sub.2 Q and --CON(CH.sub.2 --CH.sub.2).sub.2 Q or
- (e) perfluoro-C.sub.1 -C.sub.4 -alkyl;
- R.sup.10 is:
- (a) aryl, where aryl is as defined in R.sup.4 (c) above,
- (b) heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above,
- (c) C.sub.1 -C.sub.6 -alkyl, wherein alkyl is unsubstimted or substituted with a substituent selected from the group consisting of:
- aryl, where aryl is as defined in R.sup.4 (c) above, heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above, --OH,--NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, --CO.sub.2 R.sup.7, Cl, Br, F, I, and --CF.sub.3, or
- (d) perfluoro-C.sub.1 -C.sub.4 -alkyl;
- R.sup.11 is:
- C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, --CONR.sup.7 R.sup.8, heteroaryl, where heteroaryl is as defined in R.sup.4 (d) above, phenyl, --CO--C.sub.3 -C.sub.7 -cycloalkyl, or --CO--C.sub.1 -C.sub.6 -alkyl;
- and
- r is:
- 1or2.
106 more elements
A compound of structural formula ##STR20## wherein the substituents are as defined in Table 1 below and Boc is defined as N-tert-butoxycarbonyl and Ac is defined as acetyl:
- TABLE I ______________________________________ R.sup.4 R.sup.5 R.sup.6 R.sup.9 ______________________________________ H H H --(CH.sub.2).sub.5 NHBoc H H H --(CH.sub.2).sub.5 NH.sub.2 Methyl H H --(CH.sub.2).sub.5 NHBoc Methyl H H --(CH.sub.2).sub.5 NH.sub.2 n-Propyl H i-propyl --(CH.sub.2).sub.5 NHBoc n-Propyl H H --(CH.sub.2).sub.5 NHBoc n-Propyl H H --(CH.sub.2).sub.5 NH.sub.2 i-Propyl H H cyclopropyl i-Propyl H H --(CH.sub.2).sub.4 NHBoc i-Propyl H H --(CH.sub.2).sub.4 NH.sub.2 Phenyl H H cyclopropyl Phenyl H H --(CH.sub.2).sub.5 NHBoc Phenyl H H --(CH.sub.2).sub.5 NH.sub.2 Phenyl methyl H --(CH.sub.2).sub.5 NHBoc Phenyl methyl H --(CH.sub.2).sub.5 NH.sub.2 p-Toluyl H H --(CH.sub.2).sub.5 NHCOCH.sub.3 p-Toluyl H methyl --(CH.sub.2).sub.5 NH.sub.2 p-Toluyl H methyl --(CH.sub.2).sub.5 NHBoc 4-Cl-Phenyl H H --(CH.sub.2).sub.5 NHBoc 4-Cl-Phenyl H H --(CH.sub.2).sub.5 NH.sub.2 4-Cl-Phenyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 4-Cl-Phenyl H methyl --(CH.sub.2).sub.5 NHBoc 4-Br-Phenyl H H --(CH.sub.2).sub.5 NHBoc 4-Br-Phenyl H H --(CH.sub.2).sub.5 NH.sub.2 4-F-Phenyl H H --(CH.sub.2).sub.5 NHBoc 4-F-Phenyl H H --(CH.sub.2).sub.5 NH.sub.2 4-OMe-Phenyl H H --(CH.sub.2).sub.5 NHBoc 4-OMe-Phenyl H H --(CH.sub.2).sub.5 NH.sub.2 p-Toluyl H H --(CH.sub.2).sub.5 NHBoc p-Toluyl H H --(CH.sub.2).sub.5 NH.sub.2 p-Toluyl H H --(CH.sub.2).sub.6 NHBoc p-Toluyl H H --(CH.sub.2).sub.6 NH.sub.2 p-Toluyl H H --(CH.sub.2).sub.3 NHBoc p-Toluyl H H --(CH.sub.2).sub.3 NH.sub.2 p-Toluyl H H --(CH.sub.2).sub.4 NHBoc P-Toluyl B H --(CH.sub.2).sub.4 NH.sub.2 p-Toluyl H H --(CH.sub.2).sub.6 OH p-Toluyl H H --(CH.sub.2).sub.5 COOC.sub.2 H.sub.5 p-Toluyl H H --(CH.sub.2).sub.4 COOH p-Toluyl methyl H --(CH.sub.2).sub.5 COOC.sub.2 H.sub.5 p-Toluyl H H --(CH.sub.2).sub.6 CH.sub.3 p-Toluyl H H --(CH.sub.2).sub.5 CONHCH.sub.3 p-Toluyl H H --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2 p-Toluyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 p-Toluyl H H --(CH.sub.2).sub.4 CON(CH.sub.2).sub.4 p-Toluyl H H --(CH.sub.2).sub.4 CON(CH.sub.2).sub.5 p-Toluyl H H --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2 O p-Toluyl H H --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2 NH p-Toluyl H H --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2 NAc p-Toluyl H H --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2 NCH.sub.3 p-Toluyl H H --(CH.sub.2).sub.6 CON(CH.sub.3).sub.2 p-Toluyl H H --(CH.sub.2).sub.2 CH(NHBoc)COOtBu p-Toluyl H H 2-thienyl p-Toluyl H H 3-furyl p-Toluyl H H 2-furyl p-Toluyl H H --(CH.sub.2).sub.2 OCH.sub.3 p-Toluyl H H --NH(CH.sub.2).sub.3 CH.sub.3 p-Toluyl H H --NH(CH.sub.2).sub.5 CH.sub.3 p-Toluyl H H --NH(CH.sub.2).sub.3 Cl p-Toluyl H H --NH(CH.sub.2).sub.2 -2-thienyl p-Toluyl H H --CH.sub.2 OCH.sub.2 CH.sub.3 p-Toluyl H H --(CH.sub.2).sub.5 OH p-Toluyl H H --NH(CH.sub.2).sub.5 CH.sub.3 p-Toluyl H H --(CH.sub.2).sub.5 N(CH.sub.3).sub.2 p-Toluyl H H --(CH.sub.2).sub.5 NHCH.sub.3 1-Naphthyl H H --(CH.sub.2).sub.5 N(CH.sub.3).sub.2 1-Naphthyl H H --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2 1-Naphthyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 1-Naphthyl H H --(CH.sub.2).sub.5 NHBoc 1-Naphthyl H H --(CH.sub.2).sub.5 NH.sub.2 4-OMe-Phenyl H H --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2 4-OMe-Phenyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 2-Naphthyl H H --(CH.sub.2).sub.5 N(CH.sub.3).sub.2 2-Naphthyl H H --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2 2-Naphthyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 2-Naphthyl H H --(CH.sub.2).sub.5 NHBoc 2-Naphthyl H H --(CH.sub.2).sub.5 NH.sub.2 Pentamethylphenyl H H --(CH.sub.2).sub.5 NH.sub.2 Pentamethylphenyl H H --(CH.sub.2).sub.5 NHBoc Pentamethylphenyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 2-pyridyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 4-pyridyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 2-Thienyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 2-pyridyl H H --(CH.sub.2).sub.5 NHBoc 2-pyridyl H H --(CH.sub.2).sub.5 NH.sub.2 2-pyridyl H H --(CH.sub.2).sub.5 N(CH.sub.3).sub.2 4-pyridyl H H --(CH.sub.2).sub.5 NHBoc 4-pyridyl H H --(CH.sub.2).sub.5 NH.sub.2 4-pyridyl H H --(CH.sub.2).sub.5 N(CH.sub.3).sub.2 4-pyridyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 2-Thienyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 4-(N-Morpholino- H H --(CH.sub.2).sub.5 NHBoc methyl)phenyl 4-(N-Morpholino- H H --(CH.sub.2).sub.5 NH.sub.2 methyl)phenyl 4-(N-Pyrrolidino- H H --(CH.sub.2).sub.5 NHBoc methyl)phenyl 4-(N-Pyrrolidino- H H --(CH.sub.2).sub.5 NH.sub.2 methyl)phenyl 4-(N-Pyrrolidino- H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 methyl)phenyl 4-(N-Morpholino- H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 methyl)phenyl p-Toluyl H H --(CH.sub.2).sub.3 CON(CH.sub.3).sub.2 p-Toluyl H H --(CH.sub.2).sub.5 NHCON(CH.sub.3).sub.2 p-Toluyl H H --(CH.sub.2).sub.5 NHSO.sub.2 iPr p-Toluyl H H --(CH.sub.2).sub.3 NHCON(CH.sub.3).sub.2 p-Toluyl H H --NH(CH.sub.2).sub.3 CON(CH.sub.3).sub.2 p-Toluyl H H --(CH.sub.2).sub.3 NHCOCH.sub.3 p-Toluyl H H --(CH.sub.2).sub.4 CONH.sub.2 p-Toluyl H H --(CH.sub.2).sub.4 CONHCH.sub.3 4-Cl-Phenyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 4-F-Phenyl H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2 2-CH.sub.3 CONH- H H --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2.-- Phenyl ______________________________________
Dependencies are inferred from the claim text.